The tropomyosin receptor kinase (hereinafter abbreviated as “Trk”) family is classified as receptor tyrosine kinases and comprises TrkA which is a high-affinity receptor of nerve growth factor (hereinafter abbreviated as NGF), TrkB which is a high-affinity receptor of brain-derived neutrophic factor (BDNF) and neurotrophin (hereinafter abbreviated as NT)-4/5 and TrkC which is a high-affinity receptor of NT-3. All Trk receptors are highly expressed in nerve tissues and are involved in differentiation and maintenance of functions of nerve cells (see Non-Patent Document 1). Meanwhile it has been known that activation of TrkA in peripheral nerves by NGF initiates hyperalgesia (see Non-Patent Document 2) and based on clinical and non-clinical test results using anti-NGF antibodies and non-clinical test results using low-molecular weight Trk inhibitors, involvement of TrkA has been reported in nociceptive pain of osteoarthritis, chronic low back pain, rheumatoid arthritis, bone fracture, interstitial cystitis and chronic pancreatitis, neuropathic pain as well as cancer pain combining both types of pain described above (see Non-Patent Document 3 to 10). Moreover, Trk receptors are expressed on cancer cells such as neuroblastoma, prostate cancer and pancreatic cancer, inflammatory cells such as mast cells and eosinophils, immunocompetent cells such as T cells and B cells and keratinocytes and are reported to be potentially involved in proliferation, migration and metastasis of cancer cells, inflammatory diseases such as ulcerative colitis and Crohn's disease, allergic diseases such as asthma, rhinitis and atopic dermatitis and other diseases such as psoriasis (see Non-Patent Document 11 to 15). Therefore compounds having Trk-inhibiting activity may be applied to therapy of nociceptive pain, neuropathic pain and pain combining both types of pain, cancer, inflammatory diseases, allergic diseases and psoriasis.
Accordingly it is expected that development of Trk-inhibiting agents may provide novel types of prophylactic and/or therapeutic agents for pain and the like.
Meanwhile Patent Document 1 discloses a method for treating or preventing a disease in a human or other mammal regulated by tyrosine kinase, comprising administering, to a human or other mammal in need thereof, a compound of the following formula (Ia), a salt thereof, an isomer thereof or a prodrug.
The general formula (Ia) is as follows:

wherein Aa is selected from the group consisting of the following (i) to (iii) and the like;
(i) phenyl, optionally substituted with 1 to 3 substituents independently selected from the group consisting of Ra1, ORa1, a halogen and the like;
(ii) naphthyl, optionally substituted with 1 to 3 substituents independently selected from the group consisting of Ra1, ORa1, a halogen and the like;
(iii) a 5- to 6-membered monocyclic heteroaryl group, optionally substituted with 1 to 3 substituents independently selected from the group consisting of Ra1, ORa1, a halogen and the like and having 1 to 3 heteroatoms independently selected from the group consisting of O, N and S;
Ba is selected from the group consisting of the following (i) to (iii) and the like;
(i) phenyl, optionally substituted with 1 to 3 substituents independently selected from the group consisting of -La-Ma, C1-C5 linear or branched alkyl, halogen and the like;
(ii) naphthyl, optionally substituted with 1 to 3 substituents independently selected from the group consisting of -La-Ma, a C1-C5 linear or branched alkyl, a halogen and the like;
(iii) a 5- to 6-membered monocyclic heteroaryl group, optionally substituted with 1 to 3 substituents independently selected from the group consisting of -La-Ma, a C1-C5 linear or branched alkyl, a halogen and the like and having 1 to 3 heteroatoms independently selected from the group consisting of O, N and S;
La is selected from the group consisting of —(CH2)ma—O—(CH2)la—, —(CH2)ma—C(O)—(CH2)la— and the like, wherein the variables ma and la are integers independently selected from 0 to 4;
Ma is selected from the group consisting of the following (i) to (iii) and the like;
(i) phenyl, optionally substituted with 1 to 3 substituents independently selected from the group consisting of Ra1, ORa1, a halogen and the like;
(ii) naphthyl, optionally substituted with 1 to 3 substituents independently selected from the group consisting of Ra1, ORa1, a halogen and the like;
(iii) a 5- to 6-membered monocyclic heteroaryl group, optionally substituted with 1 to 3 substituents independently selected from the group consisting of Ra1, ORa1, a halogen and the like and having 1 to 3 heteroatoms independently selected from the group consisting of O, N and S;
wherein Ra1 is independently selected from the group consisting of (a) a hydrogen, (b) a C1-C6 alkyl, (c) phenyl, (d) a 5- to 6-membered monocyclic heteroaryl or a 8- to 10-membered bicyclic heteroaryl both having 1 to 4 heteroatoms selected from the group consisting of O, N and S, (e) a C1-C3 alkyl-phenyl and (f) an alkyl-heteroaryl having 1 to 4 heteroatoms selected from the group consisting of O, N and S; Ra1 is, when it is not a hydrogen, optionally substituted with 1 to 3 substituents independently selected from the group consisting of a C1-C5 linear, branched or cyclic alkyl, a C1-C3 alkoxy, hydroxy, amino, a C1-C3 alkylamino, a C2-C6 dialkylamino, a halogen, cyano and nitro; and the definitions of the groups are partially abstracted.
Patent Document 1 discloses that the compound therein inhibits KDR and thereby is used for a method of treatment of diseases mediated by VEGF induced signal transduction pathways in a human or other mammal, particularly retinopathy or retinopathy of prematurity. However, it is not disclosed or suggested that the compound disclosed therein has Trk-inhibiting activity and Patent Document 1 does not specifically disclose the present compound.
Patent Document 2 discloses that a compound represented by the general formula (Ib):

wherein:
Yb is N or CH;
Lb1 is a bond, —O—, —S—, —SO—, —SO2— or the like;
Lb2 is a bond, —NHC(O)NH—, —NHC(O)— or the like;
Rb1 is (i) Rb5 or (ii) a C1-C6 alkyl optionally substituted with one or more halogen, Rb5 or the like;
Rb2 is (i) a C1-C6 alkyl or (ii) an aryl or heteroaryl, each of which is optionally substituted with one or more halogen, Rb9, ORb9, SRb9, N(Rb9)2, C(O)Rb9 or the like;
Rb3 is a hydrogen, a halogen, a C1-C6 alkyl or the like;
Rb5 is a cycloalkyl, a heterocycle, an aryl or a heteroaryl, each of which is optionally substituted with one or more halogen, ORb6, N(Rb6)2, Rb7, ORb7 or the like;
Rb7 is a cycloalkyl, a heterocycle, an aryl or a heteroaryl, each of which is optionally substituted with one or more halogen, hydroxy, N(Rb6)2 or the like; and
each Rb6 is independently a hydrogen or a C1-C4 alkyl (the definitions of the groups are partially abstracted), a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex or a prodrug thereof acts as an endogenous utrophin upregulator. However, it is not disclosed or suggested that the compounds have Trk-inhibiting activity. In addition, Patent Document 2 does not specifically disclose the present compound.
Further, Patent Document 3 discloses that a compound represented by the general formula (Ic):

wherein:
Ac and Cc are each independently selected from the group consisting of an aryl and heteroaryl, both of which may be optionally substituted;
Bc is selected from the group consisting of —N(H)C(O)N(H)— and —N(H)C(O)N(H)CH2—;
Xc1 to Xc4 are each selected from the group consisting of C(Rc2) and N and at least one of Xc1 to Xc4 is N;
Xc5 is C(Rc3)(Rc4), N(Rc3), O or S(O)mc; and
Rc1 is selected from the group consisting of a heteroaryl and heterocycloalkyl, both of which may be optionally substituted (the definitions of the groups are partially abstracted), a salt or ester thereof or a prodrug thereof has B-Raf-inhibiting activity. However, it is not disclosed or suggested that the compounds have Trk-inhibiting activity. In addition, Patent Document 3 does not disclose the present compound.
None of the Trk-inhibiting compounds which have been known by now has a chemical structure characterized by “urea group-ring-O-ring-ring” as the compounds of the present invention.
Patent Document 1: WO 2003/068228
Patent Document 2: WO 2010/057833
Patent Document 3: WO 2007/076473
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Non-Patent Document 2: Trends in Pharmacological Sciences, 27, 85-91, 2006
Non-Patent Document 3: New England Journal of Medicine, 363, 1521-1531, 2010
Non-Patent Document 4: Pain, 152, 2248-2258, 2011
Non-Patent Document 5: Journal of Urology, 185, 1716-1721, 2011
Non-Patent Document 6: Pain, 116, 8-16, 2005
Non-Patent Document 7: Bone, 48, 389-398, 2011
Non-Patent Document 8: Molecular Pain, 6, 87, 2010
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Non-Patent Document 10: Gastroenterology, 141, 370-377, 2011
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